Several aspects of regulation of receptor signal transduction have been studied using neurohybrid NCB-20 and NG 108-15 cell lines. In NCB-20 cells, adenosine selectively inhibits histamine-induced phosphoinositide turnover with no significant effect on phosphoinositide responses to carbachol and bradykinin. This inhibition was reversible and insensitive to pertussis toxin. Similar regulation by adenosine was observed in cerebellar granule cells and the effect appears to be mediated by adenosine A1 receptors through a cyclic AMP-dependent mechanism. We also have compared molecular mechanisms underlying the heterologous up-regulation of delta opioid receptors by butyrate in NCB-20 cells and homologous up- regulation by delta receptor antagonists (naltrexone and ICI 174864) in a related neurohybrid NG 108-15 cell line. While heterologous up-regulation requires new protein synthesis, homologous up-regulation is insensitive to protein synthesis inhibitor and is associated with a marked decrease in lysosomal enzyme activity. Moreover, homologous up-regulation entails an initial down-regulation followed by an inhibition of receptor degradation. The role of protein kinase C in agonist-induced down-regulation of G i- coupled receptors (delta opioid, muscarinic cholinergic and alpha2- adrenergic receptors) is being explored using both NG 108-15 and NCB-20 cells.